Download LOs Parmicokinetics 5 - 8 - PBL-J-2015

Learning Objectives:
A Matter of Opinion
Marty Roebuck
Pharmicokinetics: Q5-8.
5.
Describe the influence of the volume of distribution on tissue
distribution of drugs.
From Pharmacokinetics 2 lecture: See 8 slides + diagrams related to Volume
of distribution
Apparent volume of distribution (Vd) is a parameter used to estimate
the distribution of a drug in the body
This is important because not all drugs distribute equally throughout
all body fluids.
Relates to how readily absorbed a drug might be in the various
“compartments”. Ie plasma v fats v interstitial water v intracellular
fluid etc.
Determined by Lipid solubility - is expressed as a constant and is
unique for each drug (compound).
Distribute to:
only plasma (3 L in a 70 kg man; 0.04 L/kg)
all extracellular fluid (=12 L; 0.17 L/kg) but not intracellular
fluid
total body water (=41 L; 0.59 L/kg)
6.
Utilise the volume of distribution to calculate body burden, verify
quantities of ingestion and calculate peak plasma concentrations.

To answer this you need to consider this equation: (see
Pharmacokinetics 2 Lect)
Vd = Q/CP =mg/kg/mg/L =L/kg
Ie:
Vol distribution(Vd) = amount in body(Q)/ concentration in
plasma(CP)

Body Burden = total amount of compound in body (Q) = Cp x Vd
(from the above equation)
Eg: Digoxin has a volume of distribution of 7L/kg. What is the peak
plasma concentration if 500µg is administered to a 12kg child.
Using above equation:
Vd = 7(L)x12(kg)=84L
Cp (plasma concentration) = 500µg (amt in body, body burden)/84L(
Vd)
=5.95ng/ml
7.
Explain the role of plasma proteins in modulating free drug
concentrations and to alter drug half-life.
For plasma binding info, also see Pharmacokinetics Lecture 2.

The degree to which a drug binds with a protein will impact upon the
availability of that drug and hence its action. Drugs that are strongly
protein-bound stay mainly in the plasma compartment.

Albumin = most common binding protein

Plasma Protein Binding (PPB) limits a drug’s “BIOAVAILABILITY”

And: Only the free drug is pharmacologically active or bioavailable

Free Drug:
- Quick action
- Freely available
- Filtered and eliminated faster.

Protein Bound Drug:
- Slow and steady effect
- Less excreted by kidneys (size impacts upon filtration)

Equilibriums exist:
-
8.
Explain risks associated with displacement of plasma protein bound
drugs.

If two drugs compete for the same site then stronger affinity will
transiently displace weaker affinity.
-

Eg:
bilirubin displaced by sulphonamides in children→crosses
BBB→kernicterus (choreoathetosis-permanent movement disorder)
Especially important if they also reduce elimination
-
-
Free v Bound
Excretion v Reabsorption
phenylbutazone displaces warfarin and also inhibits warfarin
metabolism→internal bleeding
aspirin displaces methotrexate and also reduces its renal
secretion→GIT and kidney toxicity
quinidine/verapamil/amiodarone displace digoxin and reduce its
renal excretion→severe dysrhythmias.